FLNC-related myopathy: a description of 27 patients from 21 unrelated families

Myofibrillar myopathies are inherited neuromuscular disorders characterized by protein aggregation and myofibrillar disorganization. FLNC -related myopathy, a subtype of MFM, encompasses a broad clinical spectrum ranging from limb-girdle and distal myopathies to isolated cardiomyopathy. We retrospectively collected a cohort of 27 patients with genetically confirmed FLNC- related myopathy. Mean age at first symptoms and diagnosis was 40 ± 14 and 54 ± 17 years, respectively. Among the 27 patients, 13 (48%) had proximal muscle weakness only, 3 (11%) had distal muscle weakness only, 9 (33%) had both proximal and distal weakness, and 2 (8%) had no limb weakness. Axial weakness was identified in 16 patients (59%), facial weakness in 4 patients (15%), cardiac involvement such as cardiomyopathies (hypertrophic or dilated) in 13 patients (48%), and conduction and rhythm disorders requiring an implantable cardioverter defibrillator in 2 patients. Mean value of forced vital capacity was 85 ± 28% and 3 patients with sleep apnea syndrome required nocturnal CPAP. Muscle magnetic resonance imaging showed fatty replacement mainly in thigh muscles affecting the posterior compartment, pelvic girdle, and paravertebral muscles. Mean creatine kinase value was 502 ± 436 U/L. Muscle biopsy showed muscle fiber size variability, intracytoplasmic protein aggregates, internalized nuclei, rimmed vacuoles and type 1 muscle fiber predominance. FLNC gene analysis identified heterozygous missense and nonsense variants in 22 (81%) and 3 (11%) patients respectively, and a complex deletion insertion variant in 2 patients (7%). This study reports one of the largest multicenter cohorts of FLNC -related myopathy, confirming that the disease most frequently presents as an adult-onset proximal myopathy with frequent cardiac involvement. We also identified a relatively consistent MRI pattern mainly involving the posterior thigh and paravertebral muscles. Despite the predominance of missense FLNC variants, substantial clinical and pathological heterogeneity was observed, with no clear genotype–phenotype correlation.